Jessica Lawrence

Assessment of GS-9219 in a Pet Dog Model of Non-Hodgkin's Lymphoma

Purpose: To assess, in dogs with naturally occurring non-Hodgkins lymphoma, pharmacokinetics, safety, and activity of GS-9219, a prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG), which delivers PMEG and its phosphorylated metabolites to lymphoid cells with preferential cytotoxicity in cells with a high proliferation index such as lymphoid malignancies. Experimental Design: To generate proof-of-concept, a phase I/II trial was conducted in pet dogs (n = 38) with naturally occurring non-Hodgkins lymphoma using different dose schedules of GS-9219. A subset of dogs was further evaluated with 3′-deoxy-3′-18F-fluorothymidine positron emission tomography/computed tomography imaging before and after treatment. Results: The prodrug had a short plasma half-life but yielded high and prolonged intracellular levels of the cytotoxic metabolite PMEG diphosphate in peripheral blood mononuclear cells in the absence of detectable plasma PMEG. Dose-limiting toxicities were generally manageable and reversible and included dermatopathy, neutropenia, and gastrointestinal signs. Antitumor responses were observed in 79% of dogs and occurred in previously untreated dogs and dogs with chemotherapy-refractory non-Hodgkins lymphoma. The median remission durations observed compare favorably with other monotherapies in dogs with non-Hodgkins lymphoma. High 3′-deoxy-3′-18F-fluorothymidine uptake noted in lymphoid tissues before treatment decreased significantly after treatment (P = 0.016). Conclusions: GS-9219 was generally well tolerated and showed significant activity against spontaneous non-Hodgkins lymphoma as modeled in pet dogs and, as such, supports clinical evaluation in humans.

PET/CT today and tomorrow in veterinary cancer diagnosis and monitoring: fundamentals, early results and future perspectives

Functional imaging using positron emission tomography (PET) plays an important role in the diagnosis, staging, image-guided treatment planning and monitoring of malignant diseases. PET imaging complements conventional anatomical imaging such as computed tomography (CT) and magnetic resonance imaging (MRI). The strength of CT scanning lies in its high spatial resolution, allowing for anatomical characterization of disease. PET imaging, however, moves beyond anatomy and characterizes tissue based on functions such as metabolic rate. Combined PET/CT scanners were introduced commercially in 2001 and a number of technological advancements have since occurred. Radiolabelled tracers such as (18)F-fluorodeoxyglucose (FDG) and (18)F-fluorothymidine (FLT) allow visualization of various metabolic processes within cancer cells. Many studies in human oncology evaluating the utility of PET/CT have demonstrated clinical benefits. Few veterinary studies have been performed, but initial studies show promise for improved detection of malignancy, more thorough staging of canine cancer and determination of early response and disease recrudescence.

Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells

Dysregulation of platelet-derived growth factor receptor (PDGFR) may play a role in feline injection-site sarcoma (ISS) cell growth and viability. Masitinib, a tyrosine kinase inhibitor approved for treatment of canine mast cell tumours, is highly selective for the PDGFR signalling pathway and may offer a new therapeutic approach for this disease. The in vitro effects of masitinib on growth, apoptosis and PDGFR signalling in two novel ISS cell lines were investigated. PDGFR expression was confirmed by Western blot in cell lines derived from a primary ISS tumour (JB) and a corresponding, histologically confirmed ISS lung metastasis (JBLM). Masitinib inhibited cell growth and PDGFR phosphorylation in both cell lines. Higher drug concentrations were required to inhibit growth than to modulate ligand-induced autophosphorylation of PDGFR. These in vitro data suggest that masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS.

Four-fraction radiation therapy for macroscopic soft tissue sarcomas in 16 dogs

A retrospective study of 16 dogs with macroscopic soft tissue sarcomas was performed to evaluate response to a four-fraction radiotherapy protocol (prescribed dose of 32 Gy). Radiation was well tolerated with minimal side effects. The overall response rate was 50%, with seven partial responses and one complete response. The median time to progression was 155 days, and the median survival time was 309 days. Coarsely fractionated radiation therapy may be a reasonable palliative option for dogs with unresectable soft tissue sarcomas, although the response is relatively short-lived.

SURVIVAL TIMES FOR CANINE INTRANASAL SARCOMAS TREATED WITH RADIATION THERAPY: 86 CASES (1996-2011)

Sarcomas comprise approximately one-third of canine intranasal tumors, however few veterinary studies have described survival times of dogs with histologic subtypes of sarcomas separately from other intranasal tumors. One objective of this study was to describe median survival times for dogs treated with radiation therapy for intranasal sarcomas. A second objective was to compare survival times for dogs treated with three radiation therapy protocols: daily-fractionated radiation therapy; Monday, Wednesday, and Friday fractionated radiation therapy; and palliative radiation therapy. Medical records were retrospectively reviewed for dogs that had been treated with radiation therapy for confirmed intranasal sarcoma. A total of 86 dogs met inclusion criteria. Overall median survival time for included dogs was 444 days. Median survival time for dogs with chondrosarcoma (n = 42) was 463 days, fibrosarcoma (n = 12) 379 days, osteosarcoma (n = 6) 624 days, and undifferentiated sarcoma (n = 22) 344 days. Dogs treated with daily-fractionated radiation therapy protocols; Monday, Wednesday and Friday fractionated radiation therapy protocols; and palliative radiation therapy protocols had median survival times of 641, 347, and 305 days, respectively. A significant difference in survival time was found for dogs receiving curative intent radiation therapy vs. palliative radiation therapy (P = 0.032). A significant difference in survival time was also found for dogs receiving daily-fractionated radiation therapy vs. Monday, Wednesday and Friday fractionated radiation therapy (P = 0.0134). Findings from this study support the use of curative intent radiation therapy for dogs with intranasal sarcoma. Future prospective, randomized trials are needed for confirmation of treatment benefits.

Species differences in tumour responses to cancer chemotherapy.

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.

Identifying the dominant prostate cancer focal lesion using image analysis and planning of a simultaneous integrated stereotactic boost

ABSTRACT Background. Prostate cancer is now the only solid organ cancer in which therapy is commonly applied to the whole gland. One of the main challenges in adopting focal boost or true focal therapy is in the accurate mapping of cancer foci defined on magnetic resonance (MR) images onto the computerised tomography (CT) images used for radiotherapy planning. Material and methods. Prostate cancer patients (n = 14) previously treated at the Edinburgh Cancer Centre (ECC) were selected for this study. All patients underwent MR scanning for the purpose of diagnosis and staging. Patients received three months of androgen deprivation hormone therapy followed by a radiotherapy planning CT scan. The dominant focal prostate lesions were identified on MR scans by a radiologist and a novel image analysis approach was used to map the location of the dominant focal lesion from MR to CT. An offline planning study was undertaken on suitable patients (n = 7) to investigate boosting of the radiation dose to the tumour using a stereotactic ablative body radiotherapy (SABR) technique. Results. The non-rigid registration algorithm showed clinically acceptable estimates of the location of the dominant focal disease on all CT image data of patients suitable for a boost treatment. Standard rigid registration was found to produce unacceptable estimates of the dominant focal lesion on CT. A SABR boost dose of 47.5 Gy was delivered to the dominant focal lesion of all patients whilst meeting all dose-volume histogram (DVH) constraints. Normal tissue complication probability (NTCP) for the rectum decreased from 1.28% to 0.73% with this method. Conclusions. These preliminary results demonstrate the potential of this image analysis method for reliably mapping dominant focal disease within the prostate from MR images onto planning CT images. Significant dose escalation using a simultaneous integrated SABR boost was achieved in all patients.

The European canine lymphoma network: a joining initiative to generate consensus guidelines for the diagnosis and therapy in canine lymphoma and research partnership

The diagnostic and therapeutic approaches to canine lymphoma are currently poorly standardized, and vary between different institutions. By comparison, in human medicine, guidelines to standardize the medical approach to patient care are published regularly and also international conferences are organized to review these guidelines.1–3 For canine lymphoma, one consensus document evaluating response to treatment has been published4 recently but few others guidelines are available,5 meaning that many approaches are based upon the opinions of individual experts. However, regular updates reflecting emerging techniques or discoveries are rarely carried out. The European Canine Lymphoma Network (ECLN) was established in 2009 as a joint initiative of the Universities of Vienna and Milan. The aim were defining common research targets, harmonizing laboratory protocols as a pre-requisite to the validation of specific diagnostic tools, and establishing effective collaborations and integrated prospective research projects amongst interested individuals. A website (www.eu-can-lymph.net) was created and more than 70 researchers from 25 European different institutions were surveyed. In June 2013, the 1st Meeting of the ECLN was organized in Switzerland during the 12th International Conference on Malignant Lymphoma. More than 160 participants, including human and veterinary clinicians from 15 different countries, attended.6 The workshop established high-priority at the need to create canine lymphoma consensus guidelines encompassing the most up-to-date diagnostic and therapeutic approaches, also drawing comparisons with the human counterpart, as a first step. In collaboration with Solaris CRO, a contract research organization, a new webpage, logo and a dedicated platform (Consensus Platfom) specifically designed to facilitate the creation of such documents were created. In September 2013, the process of recruiting researchers and clinicians to the ECLN began, and, currently collecting more than 120 researchers in one year, is still ongoing. The first documents regarding the ECLN’s constitution and intellectual property rights were produced. The Consensus Platform is comprised of two working groups (WGs; Fig. 1), a diagnostic group (WG1) and a therapeutic group (WG2) that are coordinated by an appointed Chairperson (WG Chair). The WG1 was further composed by six panels comprising: cytology, histopathology, flow cytometry, molecular biology/genetics, biomarkers and imaging, whereas WG2 was divided in B-cell lymphoma, T-cell lymphoma, extranodal lymphoma, clinical trials and pharmacotoxicology, and immunotherapy panels. Each panel was further composed by a number of Chairs and Editors. By regulation the panel Chair coordinates the work of the Editors and maintains contact with the WG Chair and the platform administrator. Within each panel, the members, either Participants or Auditors, were selected through review of individual curriculum vitae. A participant had to demonstrate sufficient experience relevant to the panel topic allowing him/her to take part in future forum discussions and to vote on the content of consensus documents. Auditors, although lacking specific experience in a particular field, are permitted to attend all steps of the creation of a consensus document but cannot vote specifically on the content of written materials. Members with a potential conflict of interest or belonging to the same institution as another Participant are relegated to the role of Auditors, thereby avoiding any possible bias in the voting process. Finally, 2–3 external reviewers were appointed to each panel to act as specialist editors. These individuals were chosen because they were non-European but internationally recognized veterinary experts

Changes in γ-H2AX expression in irradiated feline sarcoma cells: An indicator of double strand DNA breaks

Feline injection site sarcoma (ISS) is a highly invasive soft tissue tumor that is commonly treated with radiation. Cellular deoxyribonucleic acid (DNA) is the principal target for the biologic effects of radiation with cell killing correlating to the number of double stranded DNA breaks (DSBs). The objective of this study was to determine if radiation-induced damage to feline ISS cells could be detected using a commercially available DNA DSB detection kit. Feline ISS cells were irradiated and evaluated for extent of DSB induction with a γ-H2AX chemiluminescent kit; results were validated by Western Blot analysis. Irradiated cells showed a significant increase in double strand break induction compared to control cells, which was supported by Western Blot. DNA damage in feline sarcoma cells following single exposure of radiation can be indirectly detected using a commercially available mouse anti-human monoclonal antibody for γ-H2AX.

Image-guided transnasal cryoablation of a recurrent nasal adenocarcinoma in a dog

An eight-year-old female spayed Airedale terrier with rapid recurrence of a nasal adenocarcinoma following image-guided intensity-modulated radiation therapy was treated with transnasal, image-guided cryotherapy. Ice ball size and location were monitored real-time with computed tomography-fluoroscopy to verify that the entire tumour was enveloped in ice. Serial computed tomography scans demonstrated reduction in and subsequent resolution of the primary tumour volume corresponding visually with the ice ball imaged during the ablation procedure. Re-imaging demonstrated focallysis of the cribriform plate following ablation that spontaneously resolved by 13 months. While mild chronic nasal discharge developed following cryoablation, no other clinical signs of local nasal neoplasia were present. Twenty-one months after nasal tumour cryoablation the dog was euthanased as a result of acute haemoabdomen. Image-guided cryotherapy may warrant further investigation for the management of focal residual or recurrent tumours in dogs, especially in regions where critical structures preclude surgical intervention.